ArticleThe journal of physical chemistry. B2018
Arl2-Mediated Allosteric Release of Farnesylated KRas4B from Shuttling Factor PDEδ.
Article in The journal of physical chemistry. B, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 15 citations in OpenAlex.
- Pioneer in Molecular Biology: Conformational Ensembles in Molecular Recognition, Allostery, and Cell Function.Journal of molecular biology · 2025Review
- The mechanism of activation of MEK1 by B-Raf and KSR1.Cellular and molecular life sciences : CMLS · 2022Article
- Targeted delivery of a PROTAC induced PDEδ degrader by a biomimetic drug delivery system for enhanced cytotoxicity against pancreatic cancer cells.American journal of cancer research · 2022Article
- The structural basis of Akt PH domain interaction with calmodulin.Biophysical journal · 2021Article
- Mechanistic Differences of Activation of Rac1The journal of physical chemistry. B · 2021Article
- Regulation of ARL2 in colorectal cancer cell proliferation and tumorigenicity, and its negative association with AXL.Oncology letters · 2021Article
- The mechanism of activation of monomeric B-Raf V600E.Computational and structural biotechnology journal · 2021Article
- The quaternary assembly of KRas4B with Raf-1 at the membrane.Computational and structural biotechnology journal · 2020Article
- The Structural Basis of the Farnesylated and Methylated KRas4B Interaction with Calmodulin.Structure (London, England : 1993) · 2019Article
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Authors and funding
5 authors at 2 institutions in 3 countries.
Funding
Abstract
Proper localization of Ras proteins at the plasma membrane (PM) is crucial for their functions. To get to the PM, KRas4B and some other Ras family proteins bind to the PDEδ shuttling protein through their farnesylated hypervariable regions (HVRs). The docking of their farnesyl (and to a lesser extent geranylgeranyl) in the hydrophobic pocket of PDEδ's stabilizes the interaction. At the PM, guanosine 5'-triphosphate (GTP)-bound Arf-like protein 2 (Arl2) assists in the release of Ras from the PDEδ. However, exactly how is still unclear. Using all-atom molecular dynamics simulations, we unraveled the detailed mechanism of Arl2-mediated release of KRas4B, the most abundant oncogenic Ras isoform, from PDEδ. We simulated ternary Arl2-PDEδ-KRas4B HVR complexes and observed that Arl2 binding weakens the PDEδ-farnesylated HVR interaction. Our detailed analysis showed that allosteric changes (involving β6 of PDEδ and additional PDEδ residues) compress the hydrophobic PDEδ pocket and push the HVR out. Mutating PDEδ residues that mediate allosteric changes in PDEδ terminates the release process. Mutant Ras proteins are enriched in human cancers, with currently no drugs in the clinics. This mechanistic account may inspire efforts to develop drugs suppressing oncogenic KRas4B release.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.